Project Summary This application is for F30 support of Lindsay Stoyka during the laboratory phase of her MD/PhD training. The scientific focus of the proposal is to examine how endogenous microtubule binding protein tau interacts with pathologic variants of alpha-synuclen to lead to cellular dysfunction and death, alpha-synuclein aggregation, and cognitive decline in Dementia with Lewy Bodies (DLB). DLB is the second most common cognitive disorder in the elderly and is characterized by fluctuating cognitive performance, visuospatial impairment, and frontosubcortical dysfunction. Intracellular aggregates of alpha-synuclein (termed Lewy bodies) are found in neurons throughout the deep cortical layers, paralimbic, and neocortical structures of DLB patients. The rationale behind the present proposal is that tau has been shown to bind to alpha-synuclein fibrils, but not monomer, suggesting a pathogenic interaction that is nonexistent in the non-diseased state. Additionally, Lewy body presence in the basal forebrain and limbic areas correlate with deteriorating cognitive function in humans. A clear synergistic effect of pathogenic alpha-synuclein and tau have been shown both in vitro and in vivo. However, few studies have explored the role of endogenous tau on alpha-synuclein aggregation in a DLB model. Determining the mechanisms at play in Lewy Body formation will facilitate the development of appropriate and specific therapies for DLB patients. The proposed training plan for Lindsay Stoyka is sponsored by her project mentors, Dr. David Standaert and Dr. Volpicelli-Daley. The overall goal of the training plan is to provide the PI with a solid foundation for a successful career as a physician scientist. A project based both in translational approaches, while focused on a disease-oriented pathogenesis, is the ideal training environment for any aspiring physician scientist. Included in the training plan are experiences that help the PI: 1) gain competence in a variety of techniques in neurobiology 2) collaborate with other scientists, 3) develop hypothesis-driven research, 4) present data in a written and oral format, 5) effectively integrate research with clinic, and 6) responsibly conduct research.